title: The molecular diversity of Luminal A breast tumors.
abstract: Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options. Luminal A breast cancer is the most heterogeneous, both molecularly and clinically. Using genomic data from over 1,000 Luminal A tumors from multiple studies, we analyzed the copy number and mutational landscape of this tumor subtype. This integrated analysis revealed four major subtypes defined by distinct copy-number and mutation profiles. We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis. Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes. Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT. These rare alterations were the most prevalent in Luminal A tumors and may predict resistance to endocrine therapy. Our work provides for a further molecular stratification of Luminal A breast tumors, with potential direct clinical implications.
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, ciriello@cbio.mskcc.org.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciriello
authors.forename: Rileen
authors.initials: R
authors.lastname: Sinha
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.forename: Anders S
authors.initials: AS
authors.lastname: Jacobsen
authors.forename: Boris
authors.initials: B
authors.lastname: Reva
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D018628:Gene Dosage; D015870:Gene Expression; D042822:Genomic Instability; D006801:Humans; D053208:Kaplan-Meier Estimate; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human